Neuroprotection by Drugs, Nutraceuticals and Physical Activity

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomedicines biomedicines	4.7	3.7	2013	15.4 Days	CHF 2600
Current Issues in Molecular Biology cimb	3.1	2.4	1999	13.5 Days	CHF 2200
International Journal of Molecular Sciences ijms	5.6	7.8	2000	16.3 Days	CHF 2900
Neurology International neurolint	3.0	2.2	2009	23.3 Days	CHF 1600
Pharmaceuticals pharmaceuticals	4.6	4.7	2004	14.6 Days	CHF 2900

7 pages, 220 KiB

Open AccessEditorial

by Andrea Tarozzi and Cristina Angeloni

Int. J. Mol. Sci. 2023, 24(4), 3176; https://doi.org/10.3390/ijms24043176 - 06 Feb 2023

Cited by 1 | Viewed by 1529

Acute and chronic neural injuries, including stroke, brain trauma and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Parkinson’s disease (PD), and Alzheimer’s disease (AD) are associated with high morbidity and mortality rates [...] Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

26 pages, 4093 KiB

Open AccessArticle

Neuroprotective Effects of Some Nutraceuticals against Manganese-Induced Parkinson’s Disease in Rats: Possible Modulatory Effects on TLR4/NLRP3/NF-κB, GSK-3β, Nrf2/HO-1, and Apoptotic Pathways

by Karema Abu-Elfotuh, Ahmed Mohsen Elsaid Hamdan, Asmaa A. Mohammed, Ahmed M. Atwa, Magy R. Kozman, Amany M. Ibrahim, Shaimaa M. Motawea, Heba Mohammed Refat M. Selim, Sally Tohamy Kamal Tohamy, Mahmoud Nour El-Din, Sameh S. Zaghlool, Ayah M. H. Gowifel and Magdy M. Awny

Pharmaceuticals 2022, 15(12), 1554; https://doi.org/10.3390/ph15121554 - 14 Dec 2022

Cited by 11 | Viewed by 2638

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting the substantia nigra where functions controlling body movement take place. Manganese (Mn) overexposure is linked to a neurologic syndrome resembling PD. Sesamol, thymol, wheat grass (WG), and coenzyme Q10 (CoQ10) are potent antioxidants, anti-inflammatory, [...] Read more.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting the substantia nigra where functions controlling body movement take place. Manganese (Mn) overexposure is linked to a neurologic syndrome resembling PD. Sesamol, thymol, wheat grass (WG), and coenzyme Q10 (CoQ10) are potent antioxidants, anti-inflammatory, and anti-apoptotic nutraceuticals. We investigated the potential protective effects of these nutraceuticals alone or in combinations against MnCl₂-induced PD in rats. Seven groups of adult male Sprague Dawley rats were categorized as follows: group (I) was the control, while groups 2–7 received MnCl₂ either alone (Group II) or in conjunction with oral doses of sesamol (Group III), thymol (Group IV), CoQ10 (Group V), WG (Group VI), or their combination (Group VII). All rats were subjected to four behavioral tests (open-field, swimming, Y-maze, and catalepsy tests). Biochemical changes in brain levels of monoamines, ACHE, BDNF, GSK-3β, GABA/glutamate, as well as oxidative stress, and apoptotic and neuroinflammatory biomarkers were evaluated, together with histopathological examinations of different brain regions. Mn increased catalepsy scores, while decreasing neuromuscular co-ordination, and locomotor and exploratory activity. It also impaired vigilance, spatial memory, and decision making. Most behavioral impairments induced by Mn were improved by sesamol, thymol, WG, or CoQ10, with prominent effect by sesamol and thymol. Notably, the combination group showed more pronounced improvements, which were confirmed by biochemical, molecular, as well as histopathological findings. Sesamol or thymol showed better protection against neuronal degeneration and some behavioral impairments induced by Mn than WG or CoQ10, partly via interplay between Nrf2/HO-1, TLR4/NLRP3/NF-κB, GSK-3β and Bax/Bcl2 pathways. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Graphical abstract

14 pages, 1625 KiB

Open AccessArticle

Milmed Yeast Alters the LPS-Induced M1 Microglia Cells to Form M2 Anti-Inflammatory Phenotype

by Federica Armeli, Beatrice Mengoni, Elisa Maggi, Cristina Mazzoni, Adele Preziosi, Patrizia Mancini, Rita Businaro, Thomas Lenz and Trevor Archer

Biomedicines 2022, 10(12), 3116; https://doi.org/10.3390/biomedicines10123116 - 02 Dec 2022

Cited by 4 | Viewed by 1678

Abstract

Microglial cells polarized towards a proinflammatory phenotype are considered the main cellular players of neuroinflammation, underlying several neurodegenerative diseases. Many studies have suggested that imbalance of the gut microbial composition is associated with an increase in the pro-inflammatory cytokines and oxidative stress that [...] Read more.

Microglial cells polarized towards a proinflammatory phenotype are considered the main cellular players of neuroinflammation, underlying several neurodegenerative diseases. Many studies have suggested that imbalance of the gut microbial composition is associated with an increase in the pro-inflammatory cytokines and oxidative stress that underlie chronic neuroinflammatory diseases, and perturbations to the gut microbiota were detected in neurodegenerative conditions such as Parkinson’s disease and Alzheimer’s disease. The importance of gut-brain axis has been uncovered and the relevance of an appropriate microbiota balance has been highlighted. Probiotic treatment, rebalancing the gut microbioma, may reduce inflammation. We show that Milmed yeast, obtained from S. cerevisiae after exposure to electromagnetic millimeter wavelengths, induces a reversal of LPS-M1 polarized microglia towards an anti-inflammatory phenotype, as demonstrated morphologically by the recovery of resting phenotype by microglia, by the decrease in the mRNAs of IL-1β, IL-6, TNF-α and in the expression of iNOS. Moreover, Milmed stimulated the secretion of IL-10 and the expression of Arginase-1, cell markers of M2 anti-inflammatory polarized cells. The present findings data suggest that Milmed may be considered to be a probiotic with diversified anti-inflammatory activity, capable of directing the polarization of microglial cells. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

13 pages, 8506 KiB

Open AccessArticle

The Neuroprotective Effects of Arecae Pericarpium against Glutamate-Induced HT22 Cell Cytotoxicity

by Yun Hee Jeong, You-Chang Oh, Tae In Kim, Jong-Sup Bae and Jin Yeul Ma

Curr. Issues Mol. Biol. 2022, 44(12), 5902-5914; https://doi.org/10.3390/cimb44120402 - 27 Nov 2022

Cited by 2 | Viewed by 1407

Abstract

Arecae Pericarpium has been found to exert anti-migraine, antidepressant, and antioxidative effects. However, the mechanisms involved are unclear. This study explored the possibility that Arecae Pericarpium ethanol extract (APE) exerts neuroprotective effects against oxidative stress-induced neuronal cell death. Since glutamate excitotoxicity has been [...] Read more.

Arecae Pericarpium has been found to exert anti-migraine, antidepressant, and antioxidative effects. However, the mechanisms involved are unclear. This study explored the possibility that Arecae Pericarpium ethanol extract (APE) exerts neuroprotective effects against oxidative stress-induced neuronal cell death. Since glutamate excitotoxicity has been implicated in the pathogenesis and development of several neurodegenerative disorders, we explored the mechanisms of action of APE on oxidative stress-induced by glutamate. Our results revealed that pretreatment with APE prevents glutamate-induced HT22 cell death. APE also reduced both the levels of intracellular reactive oxygen species and the apoptosis of cells, while maintaining glutamate-induced mitochondrial membrane potentials. Western blotting showed that pretreatment with APE facilitates the upregulation of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) phosphorylation; the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2); and the production of antioxidant enzymes, including catalase, glutamate-cysteine ligase catalytic subunits, NAD(P)H quinone oxidoreductase 1, and heme oxygenase (HO)-1. The administration of LY294002, a PI3K/Akt inhibitor, attenuated the neuroprotective effects of APE on oxidative stress-induced neuronal cell damage. This allowed us to infer that the protective effects of APE on oxidative damage to cells can be attributed to the PI3K/Akt-mediated Nrf-2/HO-1 signaling pathway. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

27 pages, 4893 KiB

Open AccessArticle

Identification of a Cardiac Glycoside Exhibiting Favorable Brain Bioavailability and Potency for Reducing Levels of the Cellular Prion Protein

by Shehab Eid, Thomas Zerbes, Declan Williams, Xinzhu Wang, Chris Sackmann, Sammy Meier, Nickolai O. Dulin, Pavel Nagorny and Gerold Schmitt-Ulms

Int. J. Mol. Sci. 2022, 23(23), 14823; https://doi.org/10.3390/ijms232314823 - 26 Nov 2022

Cited by 4 | Viewed by 1820

Abstract

Several strands of investigation have established that a reduction in the levels of the cellular prion protein (PrP^C) is a promising avenue for the treatment of prion diseases. We recently described an indirect approach for reducing PrP^C levels that targets [...] Read more.

Several strands of investigation have established that a reduction in the levels of the cellular prion protein (PrP^C) is a promising avenue for the treatment of prion diseases. We recently described an indirect approach for reducing PrP^C levels that targets Na,K-ATPases (NKAs) with cardiac glycosides (CGs), causing cells to respond with the degradation of these pumps and nearby molecules, including PrP^C. Because the therapeutic window of widely used CGs is narrow and their brain bioavailability is low, we set out to identify a CG with improved pharmacological properties for this indication. Starting with the CG known as oleandrin, we combined in silico modeling of CG binding poses within human NKA folds, CG structure-activity relationship (SAR) data, and predicted blood–brain barrier (BBB) penetrance scores to identify CG derivatives with improved characteristics. Focusing on C4′-dehydro-oleandrin as a chemically accessible shortlisted CG derivative, we show that it reaches four times higher levels in the brain than in the heart one day after subcutaneous administration, exhibits promising pharmacological properties, and suppresses steady-state PrP^C levels by 84% in immortalized human cells that have been differentiated to acquire neural or astrocytic characteristics. Finally, we validate that the mechanism of action of this approach for reducing cell surface PrP^C levels requires C4′-dehydro-oleandrin to engage with its cognate binding pocket within the NKA α subunit. The improved brain bioavailability of C4′-dehydro-oleandrin, combined with its relatively low toxicity, make this compound an attractive lead for brain CG indications and recommends its further exploration for the treatment of prion diseases. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

11 pages, 2096 KiB

Open AccessArticle

Effect of Cannabidiolic Acid, N-Trans-Caffeoyltyramine and Cannabisin B from Hemp Seeds on microRNA Expression in Human Neural Cells

by Armando Di Palo, Chiara Siniscalchi, Giuseppina Crescente, Ilenia De Leo, Antonio Fiorentino, Severina Pacifico, Aniello Russo and Nicoletta Potenza

Curr. Issues Mol. Biol. 2022, 44(10), 5106-5116; https://doi.org/10.3390/cimb44100347 - 21 Oct 2022

Cited by 6 | Viewed by 1761

Abstract

Given the increasing interest in bioactive dietary components that can modulate gene expression enhancing human health, three metabolites isolated from hemp seeds—cannabidiolic acid, N-trans-caffeoyltyramine, and cannabisin B—were examined for their ability to change the expression levels of microRNAs in human [...] Read more.

Given the increasing interest in bioactive dietary components that can modulate gene expression enhancing human health, three metabolites isolated from hemp seeds—cannabidiolic acid, N-trans-caffeoyltyramine, and cannabisin B—were examined for their ability to change the expression levels of microRNAs in human neural cells. To this end, cultured SH-SY5Y cells were treated with the three compounds and their microRNA content was characterized by next-generation small RNA sequencing. As a result, 31 microRNAs underwent major expression changes, being at least doubled or halved by the treatments. A computational analysis of the biological pathways affected by these microRNAs then showed that some are implicated in neural functions, such as axon guidance, hippocampal signaling, and neurotrophin signaling. Of these, miR-708-5p, miR-181a-5p, miR-190a-5p, miR-199a-5p, and miR-143-3p are known to be involved in Alzheimer’s disease and their expression changes are expected to ameliorate neural function. Overall, these results provide new insights into the mechanism of action of hemp seed metabolites and encourage further studies to gain a better understanding of their biological effects on the central nervous system. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

22 pages, 2446 KiB

Open AccessArticle

Neuroprotective Effect of Artichoke-Based Nanoformulation in Sporadic Alzheimer’s Disease Mouse Model: Focus on Antioxidant, Anti-Inflammatory, and Amyloidogenic Pathways

by Heba A. S. El-Nashar, Haidy Abbas, Mariam Zewail, Mohamed H. Noureldin, Mai M. Ali, Marium M. Shamaa, Mohamed A. Khattab and Nehal Ibrahim

Pharmaceuticals 2022, 15(10), 1202; https://doi.org/10.3390/ph15101202 - 28 Sep 2022

Cited by 30 | Viewed by 2632

Abstract

The vast socio-economic impact of Alzheimer’s disease (AD) has prompted the search for new neuroprotective agents with good tolerability and safety profile. With its outstanding role as antioxidant and anti-inflammatory, alongside its anti-acetylcholinesterase activity, the artichoke can be implemented in a multi-targeted approach [...] Read more.

The vast socio-economic impact of Alzheimer’s disease (AD) has prompted the search for new neuroprotective agents with good tolerability and safety profile. With its outstanding role as antioxidant and anti-inflammatory, alongside its anti-acetylcholinesterase activity, the artichoke can be implemented in a multi-targeted approach in AD therapy. Moreover, artichoke agricultural wastes can represent according to the current United Nations Sustainable Development goals an opportunity to produce medicinally valuable phenolic-rich extracts. In this context, the UPLC-ESI-MS/MS phytochemical characterization of artichoke bracts extract revealed the presence of mono- and di-caffeoylquinic acids and apigenin, luteolin, and kaempferol O-glycosides with remarkable total phenolics and flavonoids contents. A broad antioxidant spectrum was established in vitro. Artichoke-loaded, chitosan-coated, solid lipid nanoparticles (SLNs) were prepared and characterized for their size, zeta potential, morphology, entrapment efficiency, release, and ex vivo permeation and showed suitable colloidal characteristics, a controlled release profile, and promising ex vivo permeation, indicating possibly better physicochemical and biopharmaceutical parameters than free artichoke extract. The anti-Alzheimer potential of the extract and prepared SLNs was assessed in vivo in streptozotocin-induced sporadic Alzheimer mice. A great improvement in cognitive functions and spatial memory recovery, in addition to a marked reduction of the inflammatory biomarker TNF-α, β-amyloid, and tau protein levels, were observed. Significant neuroprotective efficacy in dentate Gyrus sub-regions was achieved in mice treated with free artichoke extract and to a significantly higher extent with artichoke-loaded SLNs. The results clarify the strong potential of artichoke bracts extract as a botanical anti-AD drug and will contribute to altering the future medicinal outlook of artichoke bracts previously regarded as agro-industrial waste. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

17 pages, 4966 KiB

Open AccessArticle

Trio-Drug Combination of Sodium Valproate, Baclofen and Thymoquinone Exhibits Synergistic Anticonvulsant Effects in Rats and Neuro-Protective Effects in HEK-293 Cells

by Faheem Hyder Pottoo, Mohammed Salahuddin, Firdos Alam Khan, Batool Taleb Albaqshi, Mohamed S. Gomaa, Fatima S. Abdulla, Noora AlHajri and Mohammad N. Alomary

Curr. Issues Mol. Biol. 2022, 44(10), 4350-4366; https://doi.org/10.3390/cimb44100299 - 20 Sep 2022

Cited by 5 | Viewed by 2269

Abstract

Epilepsy is a chronic brain disorder, with anti-epileptic drugs (AEDs) providing relief from hyper-excitability of neurons, but largely failing to restrain neurodegeneration. We investigated a progressive preclinical trial in rats, whereby the test drugs; sodium valproate (SVP; 150 and 300 mg/kg), baclofen (BFN; [...] Read more.

Epilepsy is a chronic brain disorder, with anti-epileptic drugs (AEDs) providing relief from hyper-excitability of neurons, but largely failing to restrain neurodegeneration. We investigated a progressive preclinical trial in rats, whereby the test drugs; sodium valproate (SVP; 150 and 300 mg/kg), baclofen (BFN; 5 and 10 mg/kg), and thymoquinone (THQ; 40 and 80 mg/kg) were administered (i.p, once/day for 15 days) alone, and as low dose combinations, and subsequently tested for antiseizure and neuroprotective potential using electrical stimulation of neurons by Maximal electroshock (MES). The seizure stages were monitored, and hippocampal levels of m-TOR, IL-1β, IL-6 were measured. Hippocampal histopathology was also performed. Invitro and Insilco studies were run to counter-confirm the results from rodent studies. We report the synergistic effect of trio-drug combination; SVP (150 mg/kg), BFN (5 mg/kg) and THQ (40 mg/kg) against generalized seizures. The Insilco results revealed that trio-drug combination binds the Akt active site as a supramolecular complex, which could have served as a delivery system that affects the penetration and the binding to the new target. The potential energy of the ternary complex in the Akt active site after dynamics simulation was found to be −370.426 Kcal/mol, while the supramolecular ternary complex alone was −38.732 Kcal/mol, with a potential energy difference of −331.694 Kcal/mol, which favors the supramolecular ternary complex at Akt active site binding. In addition, the said combination increased cell viability by 267% and reduced morphological changes induced by Pentylenetetrazol (PTZ) in HEK-293 cells, which indicates the neuroprotective property of said combination. To conclude, we are the first to report the anti-convulsant and neuroprotective potential of the trio-drug combination. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

17 pages, 4115 KiB

Open AccessArticle

Kynurenine 3-Monooxygenase Interacts with Huntingtin at the Outer Mitochondrial Membrane

by Aisha M. Swaih, Carlo Breda, Korrapati V. Sathyasaikumar, Natalie Allcock, Mary E. W. Collier, Robert P. Mason, Adam Feasby, Federico Herrera, Tiago F. Outeiro, Robert Schwarcz, Mariaelena Repici and Flaviano Giorgini

Biomedicines 2022, 10(9), 2294; https://doi.org/10.3390/biomedicines10092294 - 15 Sep 2022

Cited by 3 | Viewed by 2427

Abstract

The flavoprotein kynurenine 3-monooxygenase (KMO) is localised to the outer mitochondrial membrane and catalyses the synthesis of 3-hydroxykynurenine from L-kynurenine, a key step in the kynurenine pathway (KP) of tryptophan degradation. Perturbation of KP metabolism due to inflammation has long been associated with [...] Read more.

The flavoprotein kynurenine 3-monooxygenase (KMO) is localised to the outer mitochondrial membrane and catalyses the synthesis of 3-hydroxykynurenine from L-kynurenine, a key step in the kynurenine pathway (KP) of tryptophan degradation. Perturbation of KP metabolism due to inflammation has long been associated with the pathogenesis of several neurodegenerative disorders, including Huntington’s disease (HD)—which is caused by the expansion of a polyglutamine stretch in the huntingtin (HTT) protein. While HTT is primarily localised to the cytoplasm, it also associates with mitochondria, where it may physically interact with KMO. In order to test this hypothesis, we employed bimolecular fluorescence complementation (BiFC) and found that KMO physically interacts with soluble HTT exon 1 protein fragment in living cells. Notably, expansion of the disease-causing polyglutamine tract in HTT leads to the formation of proteinaceous intracellular inclusions that disrupt this interaction with KMO, markedly decreasing BiFC efficiency. Using confocal microscopy and ultrastructural analysis, we determined KMO and HTT localisation within the cell and found that the KMO-HTT interaction is localized to the outer mitochondrial membrane. These data suggest that KMO may interact with a pool of HTT at the mitochondrial membrane, highlighting a possible physiological role for mitochondrial HTT. The KMO-HTT interaction is abrogated upon polyglutamine expansion, which may indicate a heretofore unrecognized relevance in the pathogenesis of this disorder. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

23 pages, 3578 KiB

Open AccessArticle

Neuroprotective Effects of Phytochemicals against Aluminum Chloride-Induced Alzheimer’s Disease through ApoE4/LRP1, Wnt3/β-Catenin/GSK3β, and TLR4/NLRP3 Pathways with Physical and Mental Activities in a Rat Model

by Ahmed Mohsen Elsaid Hamdan, Fatimah Hussain J. Alharthi, Ahmed Hadi Alanazi, Soad Z. El-Emam, Sameh S. Zaghlool, Kamel Metwally, Sana Abdulaziz Albalawi, Yahia S. Abdu, Reda El-Sayed Mansour, Hoda A. Salem, Zakaria Y. Abd Elmageed and Karema Abu-Elfotuh

Pharmaceuticals 2022, 15(8), 1008; https://doi.org/10.3390/ph15081008 - 17 Aug 2022

Cited by 18 | Viewed by 4245

Abstract

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder that is associated with abnormal cognition. AD is aided in its initiation and progression by hereditary and environmental factors. Aluminum (Al) is a neurotoxic agent that causes oxidative stress, which is linked to AD progression. [...] Read more.

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder that is associated with abnormal cognition. AD is aided in its initiation and progression by hereditary and environmental factors. Aluminum (Al) is a neurotoxic agent that causes oxidative stress, which is linked to AD progression. Additionally, Nrf2/HO-1, APOE4/LRP1, Wnt3/β-catenin, and TLR4/NLRP3 are the main signaling pathways involved in AD pathogenesis. Several phytochemicals are promising options in delaying AD evolution. Objectives: This study aimed at studying the neuroprotective effects of some phytochemicals as morin (MOR), thymol (TML), and thymoquinone (TMQ) on physical and mental activities (PhM) in Al chloride (AlCl₃)-induced AD rat model. Another objective was to determine the specificity of phytochemicals to AD signaling pathways using molecular docking. Methods: Eighty male Dawley rats were divided into eight groups. Each group received: saline (control group), AlCl₃, (ALAD), PhM, either alone or with a combination of MOR, TML, and/or TMQ for five weeks. Animals were then subjected to behavioral evaluation. Brain tissues were used for histopathological and biochemical analyses to determine the extent of neurodegeneration. The effect of phytochemicals on AlCl₃-induced oxidative stress and the main signaling pathways involved in AD progression were also investigated. Results: AlCl₃ caused a decline in spatial learning and memory, as well as histopathological changes in the brains of rats. Phytochemicals combined with PhM restored antioxidant activities, increased HO-1 and Nrf2 levels, blocked inflammasome activation, apoptosis, TLR4 expression, amyloide-β generation, and tau hyperphophorylation. They also brought ApoE4 and LRP1 levels back to normal and regulated Wnt3/β-catenin/GSK3β signaling pathway. Conclusions: The use of phytochemicals with PhM is a promising strategy for reducing AD by modulating Nrf2/HO-1, TLR4/NLRP3, APOE4/LRP1, and Wnt3/β-catenin/GSK-3β signaling pathways. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Graphical abstract

20 pages, 3217 KiB

Open AccessReview

ROCK and PDE-5 Inhibitors for the Treatment of Dementia: Literature Review and Meta-Analysis

by Dong-Hun Lee, Ji Young Lee, Dong-Yong Hong, Eun Chae Lee, Sang-Won Park, Yu Na Jo, Yu Jin Park, Jae Young Cho, Yoo Jin Cho, Su Hyun Chae, Man Ryul Lee and Jae Sang Oh

Biomedicines 2022, 10(6), 1348; https://doi.org/10.3390/biomedicines10061348 - 08 Jun 2022

Cited by 5 | Viewed by 2798

Abstract

Dementia is a disease in which memory, thought, and behavior-related disorders progress gradually due to brain damage caused by injury or disease. It is mainly caused by Alzheimer’s disease or vascular dementia and several other risk factors, including genetic factors. It is difficult [...] Read more.

Dementia is a disease in which memory, thought, and behavior-related disorders progress gradually due to brain damage caused by injury or disease. It is mainly caused by Alzheimer’s disease or vascular dementia and several other risk factors, including genetic factors. It is difficult to treat as its incidence continues to increase worldwide. Many studies have been performed concerning the treatment of this condition. Rho-associated kinase (ROCK) and phosphodiesterase-5 (PDE-5) are attracting attention as pharmacological treatments to improve the symptoms. This review discusses how ROCK and PDE-5 affect Alzheimer’s disease, vascular restructuring, and exacerbation of neuroinflammation, and how their inhibition helps improve cognitive function. In addition, the results of the animal behavior analysis experiments utilizing the Morris water maze were compared through meta-analysis to analyze the effects of ROCK inhibitors and PDE-5 inhibitors on cognitive function. According to the selection criteria, 997 publications on ROCK and 1772 publications on PDE-5 were screened, and conclusions were drawn through meta-analysis. Both inhibitors showed good improvement in cognitive function tests, and what is expected of the synergy effect of the two drugs was confirmed in this review. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

20 pages, 1804 KiB

Open AccessArticle

Physical Activity Rewires the Human Brain against Neurodegeneration

by Jose A. Santiago, James P. Quinn and Judith A. Potashkin

Int. J. Mol. Sci. 2022, 23(11), 6223; https://doi.org/10.3390/ijms23116223 - 02 Jun 2022

Cited by 17 | Viewed by 3469

Abstract

Physical activity may offset cognitive decline and dementia, but the molecular mechanisms by which it promotes neuroprotection remain elusive. In the absence of disease-modifying therapies, understanding the molecular effects of physical activity in the brain may be useful for identifying novel targets for [...] Read more.

Physical activity may offset cognitive decline and dementia, but the molecular mechanisms by which it promotes neuroprotection remain elusive. In the absence of disease-modifying therapies, understanding the molecular effects of physical activity in the brain may be useful for identifying novel targets for disease management. Here we employed several bioinformatic methods to dissect the molecular underpinnings of physical activity in brain health. Network analysis identified ‘switch genes’ associated with drastic hippocampal transcriptional changes in aged cognitively intact individuals. Switch genes are key genes associated with dramatic transcriptional changes and thus may play a fundamental role in disease pathogenesis. Switch genes are associated with protein processing pathways and the metabolic control of glucose, lipids, and fatty acids. Correlation analysis showed that transcriptional patterns associated with physical activity significantly overlapped and negatively correlated with those of neurodegenerative diseases. Functional analysis revealed that physical activity might confer neuroprotection in Alzheimer’s (AD), Parkinson’s (PD), and Huntington’s (HD) diseases via the upregulation of synaptic signaling pathways. In contrast, in frontotemporal dementia (FTD) its effects are mediated by restoring mitochondrial function and energy precursors. Additionally, physical activity is associated with the downregulation of genes involved in inflammation in AD, neurogenesis in FTD, regulation of growth and transcriptional repression in PD, and glial cell differentiation in HD. Collectively, these findings suggest that physical activity directs transcriptional changes in the brain through different pathways across the broad spectrum of neurodegenerative diseases. These results provide new evidence on the unique and shared mechanisms between physical activity and neurodegenerative diseases. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

25 pages, 2358 KiB

Open AccessReview

Therapeutic Targeting of Rab GTPases: Relevance for Alzheimer’s Disease

by Kate L. Jordan, David J. Koss, Tiago F. Outeiro and Flaviano Giorgini

Biomedicines 2022, 10(5), 1141; https://doi.org/10.3390/biomedicines10051141 - 16 May 2022

Cited by 9 | Viewed by 3441

Abstract

Rab GTPases (Rabs) are small proteins that play crucial roles in vesicle transport and membrane trafficking. Owing to their widespread functions in several steps of vesicle trafficking, Rabs have been implicated in the pathogenesis of several disorders, including cancer, diabetes, and multiple neurodegenerative [...] Read more.

Rab GTPases (Rabs) are small proteins that play crucial roles in vesicle transport and membrane trafficking. Owing to their widespread functions in several steps of vesicle trafficking, Rabs have been implicated in the pathogenesis of several disorders, including cancer, diabetes, and multiple neurodegenerative diseases. As treatments for neurodegenerative conditions are currently rather limited, the identification and validation of novel therapeutic targets, such as Rabs, is of great importance. This review summarises proof-of-concept studies, demonstrating that modulation of Rab GTPases in the context of Alzheimer’s disease (AD) can ameliorate disease-related phenotypes, and provides an overview of the current state of the art for the pharmacological targeting of Rabs. Finally, we also discuss the barriers and challenges of therapeutically targeting these small proteins in humans, especially in the context of AD. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

15 pages, 3684 KiB

Open AccessArticle

Mitochondrial Proteins Unveil the Mechanism by Which Physical Exercise Ameliorates Memory, Learning and Motor Activity in Hypoxic Ischemic Encephalopathy Rat Model

by Fred Gendi, Feifei Pei, Yuan Wang, Haoye Li, Jia Fu and Cheng Chang

Int. J. Mol. Sci. 2022, 23(8), 4235; https://doi.org/10.3390/ijms23084235 - 11 Apr 2022

Cited by 5 | Viewed by 3522

Abstract

Background: Physical exercise has been shown to improve cognitive and motor functions, promoting neurogenesis and demonstrating therapeutic benefits in neurodegenerative disorders. Nonetheless, it is crucial to investigate the cellular and molecular mechanisms by which this occurs. The study aimed to investigate and evaluate [...] Read more.

Background: Physical exercise has been shown to improve cognitive and motor functions, promoting neurogenesis and demonstrating therapeutic benefits in neurodegenerative disorders. Nonetheless, it is crucial to investigate the cellular and molecular mechanisms by which this occurs. The study aimed to investigate and evaluate the effect of swimming exercise on the changes of mitochondrial proteins in the brains of rats with hypoxic ischemic encephalopathy (HIE). Methods: the vertical pole and Morris water maze tests were used to assess the animals’ motor and cognitive functions, and western blot and immunofluorescence of brain tissue were used to assess the biomarkers of mitochondrial apoptosis and cristae stability in response to exercise training. Four groups of rats were used: (1) sham sedentary group (SHAM, NT), (2) sham exercise training group (SHAM, T) (3) hypoxic ischemic encephalopathy sedentary group (HIE, NT), and (4) hypoxic ischemic encephalopathy exercise training group (HIE, T). Results: animals with HIE showed motor and cognitive deficits, as well as increased apoptotic protein expression. Exercise, on the other hand, improved motor and cognitive functions while also suppressing the expression of apoptotic proteins. Conclusions: By stabilizing the mitochondrial cristae and suppressing the apoptotic cascade, physical exercise provided neuroprotection in hypoxic ischemia-induced brain injury. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

16 pages, 2078 KiB

Open AccessArticle

Melatonin-Induced Postconditioning Suppresses NMDA Receptor through Opening of the Mitochondrial Permeability Transition Pore via Melatonin Receptor in Mouse Neurons

by Takanori Furuta, Ichiro Nakagawa, Shohei Yokoyama, Yudai Morisaki, Yasuhiko Saito and Hiroyuki Nakase

Int. J. Mol. Sci. 2022, 23(7), 3822; https://doi.org/10.3390/ijms23073822 - 30 Mar 2022

Cited by 3 | Viewed by 2307

Abstract

Mitochondrial membrane potential regulation through the mitochondrial permeability transition pore (mPTP) is reportedly involved in the ischemic postconditioning (PostC) phenomenon. Melatonin is an endogenous hormone that regulates circadian rhythms. Its neuroprotective effects via mitochondrial melatonin receptors (MTs) have recently attracted attention. However, details [...] Read more.

Mitochondrial membrane potential regulation through the mitochondrial permeability transition pore (mPTP) is reportedly involved in the ischemic postconditioning (PostC) phenomenon. Melatonin is an endogenous hormone that regulates circadian rhythms. Its neuroprotective effects via mitochondrial melatonin receptors (MTs) have recently attracted attention. However, details of the neuroprotective mechanisms associated with PostC have not been clarified. Using hippocampal CA1 pyramidal cells from C57BL mice, we studied the involvement of MTs and the mPTP in melatonin-induced PostC mechanisms similar to those of ischemic PostC. We measured changes in spontaneous excitatory postsynaptic currents (sEPSCs), intracellular calcium concentration, mitochondrial membrane potential, and N-methyl-D-aspartate receptor (NMDAR) currents after ischemic challenge, using the whole-cell patch-clamp technique. Melatonin significantly suppressed increases in sEPSCs and intracellular calcium concentrations. The NMDAR currents were significantly suppressed by melatonin and the MT agonist, ramelteon. However, this suppressive effect was abolished by the mPTP inhibitor, cyclosporine A, and the MT antagonist, luzindole. Furthermore, both melatonin and ramelteon potentiated depolarization of mitochondrial membrane potentials, and luzindole suppressed depolarization of mitochondrial membrane potentials. This study suggests that melatonin-induced PostC via MTs suppressed the NMDAR that was induced by partial depolarization of mitochondrial membrane potential by opening the mPTP, reducing excessive release of glutamate and inducing neuroprotection against ischemia-reperfusion injury. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

11 pages, 457 KiB

Open AccessReview

Thymoquinone: Review of Its Potential in the Treatment of Neurological Diseases

by Faheem Hyder Pottoo, Abdallah Mohammad Ibrahim, Ali Alammar, Rida Alsinan, Mahdi Aleid, Ali Alshehhi, Muruj Alshehri, Supriya Mishra and Noora Alhajri

Pharmaceuticals 2022, 15(4), 408; https://doi.org/10.3390/ph15040408 - 27 Mar 2022

Cited by 22 | Viewed by 10947

Abstract

Thymoquinone (TQ) possesses anticonvulsant, antianxiety, antidepressant, and antipsychotic properties. It could be utilized to treat drug misuse or dependence, and those with memory and cognitive impairment. TQ protects brain cells from oxidative stress, which is especially pronounced in memory-related regions. TQ exhibits antineurotoxin [...] Read more.

Thymoquinone (TQ) possesses anticonvulsant, antianxiety, antidepressant, and antipsychotic properties. It could be utilized to treat drug misuse or dependence, and those with memory and cognitive impairment. TQ protects brain cells from oxidative stress, which is especially pronounced in memory-related regions. TQ exhibits antineurotoxin characteristics, implying its role in preventing neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. TQ’s antioxidant and anti-inflammatory properties protect brain cells from damage and inflammation. Glutamate can trigger cell death by causing mitochondrial malfunction and the formation of reactive oxygen species (ROS). Reduction in ROS production can explain TQ effects in neuroinflammation. TQ can help prevent glutamate-induced apoptosis by suppressing mitochondrial malfunction. Several studies have demonstrated TQ’s role in inhibiting Toll-like receptors (TLRs) and some inflammatory mediators, leading to reduced inflammation and neurotoxicity. Several studies did not show any signs of dopaminergic neuron loss after TQ treatment in various animals. TQ has been shown in clinical studies to block acetylcholinesterase (AChE) activity, which increases acetylcholine (ACh). As a result, fresh memories are programmed to preserve the effects. Treatment with TQ has been linked to better outcomes and decreased side effects than other drugs. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

18 pages, 11668 KiB

Open AccessArticle

IGF-1 as a Potential Therapy for Spinocerebellar Ataxia Type 3

by Yong-Shiou Lin, Wen-Ling Cheng, Jui-Chih Chang, Ta-Tsung Lin, Yi-Chun Chao and Chin-San Liu

Biomedicines 2022, 10(2), 505; https://doi.org/10.3390/biomedicines10020505 - 21 Feb 2022

Cited by 8 | Viewed by 2809

Abstract

Although the effects of growth hormone (GH) therapy on spinocerebellar ataxia type 3 (SCA3) have been examined in transgenic SCA3 mice, it still poses a nonnegligible risk of cancer when used for a long term. This study investigated the efficacy of IGF-1, a [...] Read more.

Although the effects of growth hormone (GH) therapy on spinocerebellar ataxia type 3 (SCA3) have been examined in transgenic SCA3 mice, it still poses a nonnegligible risk of cancer when used for a long term. This study investigated the efficacy of IGF-1, a downstream mediator of GH, in vivo for SCA3 treatment. IGF-1 (50 mg/kg) or saline, once a week, was intraperitoneally injected to SCA3 84Q transgenic mice harboring a human ATXN3 gene with a pathogenic expanded 84 cytosine–adenine–guanine (CAG) repeat motif at 9 months of age. Compared with the control mice harboring a 15 CAG repeat motif, the SCA3 84Q mice treated with IGF-1 for 9 months exhibited the improvement only in locomotor function and minimized degeneration of the cerebellar cortex as indicated by the survival of more Purkinje cells with a more favorable mitochondrial function along with a decrease in oxidative stress caused by DNA damage. These findings could be attributable to the inhibition of mitochondrial fission, resulting in mitochondrial fusion, and decreased immunofluorescence staining in aggresome formation and ataxin-3 mutant protein levels, possibly through the enhancement of autophagy. The findings of this study show the therapeutic potential effect of IGF-1 injection for SCA3 to prevent the exacerbation of disease progress. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

16 pages, 2147 KiB

Open AccessArticle

Expression of the Adenosine A_2A-A₃ Receptor Heteromer in Different Brain Regions and Marked Upregulation in the Microglia of the Transgenic APP_Sw,Ind Alzheimer’s Disease Model

by Alejandro Lillo, Iu Raïch, Jaume Lillo, Catalina Pérez-Olives, Gemma Navarro and Rafael Franco

Biomedicines 2022, 10(2), 214; https://doi.org/10.3390/biomedicines10020214 - 19 Jan 2022

Cited by 6 | Viewed by 2499

Abstract

Adenosine (Ado) receptors have been instrumental in the detection of heteromers and other higher-order receptor structures, mainly via interactions with other cell surface G-protein-coupled receptors. Apart from the first report of the A₁ Ado receptor interacting with the A_2A Ado receptor, [...] Read more.

Adenosine (Ado) receptors have been instrumental in the detection of heteromers and other higher-order receptor structures, mainly via interactions with other cell surface G-protein-coupled receptors. Apart from the first report of the A₁ Ado receptor interacting with the A_2A Ado receptor, there has been more recent data on the possibility that every Ado receptor type, A₁, A_2A, A_2B, and A₃, may interact with each other. The aim of this paper was to look for the expression and function of the A_2A/A₃ receptor heteromer (A_2AA₃Het) in neurons and microglia. In situ proximity ligation assays (PLA), performed in primary cells, showed that A_2AA₃Het expression was markedly higher in striatal than in cortical and hippocampal neurons, whereas it was similar in resting and activated microglia. Signaling assays demonstrated that the effect of the A_2AR agonist, PSB 777, was reduced in the presence of the A₃R agonist, 2-Cl-IB-MECA, whereas the effect of the A₃R agonist was potentiated by the A_2AR antagonist, SCH 58261. Interestingly, the expression of the heteromer was markedly enhanced in microglia from the APP_Sw,Ind model of Alzheimer’s disease. The functionality of the heteromer in primary microglia from APP_Sw,Ind mice was more similar to that found in resting microglia from control mice. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

16 pages, 2868 KiB

Open AccessArticle

Perilla frutescens Leaf Extract Attenuates Vascular Dementia-Associated Memory Deficits, Neuronal Damages, and Microglial Activation

by Hyun-Bae Kang, Shin-Hye Kim, Sun-Ho Uhm, Do-Kyung Kim, Nam-Seob Lee, Young-Gil Jeong, Nak-Yun Sung, Dong-Sub Kim, In-Jun Han, Young-Choon Yoo and Seung-Yun Han

Curr. Issues Mol. Biol. 2022, 44(1), 257-272; https://doi.org/10.3390/cimb44010019 - 08 Jan 2022

Cited by 7 | Viewed by 2634

Abstract

Vascular dementia (VaD) is characterized by a time-dependent memory deficit and essentially combined with evidence of neuroinflammation. Thus, polyphenol-rich natural plants, which possess anti-inflammatory properties, have received much scientific attention. This study investigated whether Perilla frutescens leaf extract (PFL) exerts therapeutic efficacy against [...] Read more.

Vascular dementia (VaD) is characterized by a time-dependent memory deficit and essentially combined with evidence of neuroinflammation. Thus, polyphenol-rich natural plants, which possess anti-inflammatory properties, have received much scientific attention. This study investigated whether Perilla frutescens leaf extract (PFL) exerts therapeutic efficacy against VaD. Sprague Dawley rats were divided into five groups: SO, sham-operated and vehicle treatment; OP, operated and vehicle treatment; PFL-L, operated and low-dose (30 mg/kg) PFL treatment; PFL-M, operated and medium-dose (60 mg/kg) PFL treatment; and PFL-H, operated and high-dose (90 mg/kg) PFL treatment. Two-vessel occlusion and hypovolemia (2VO/H) were employed as a surgical model of VaD, and PFL was given orally perioperatively for 23 days. The rats underwent the Y-maze, Barnes maze, and passive avoidance tests and their brains were subjected to histologic studies. The OP group showed VaD-associated memory deficits, hippocampal neuronal death, and microglial activation; however, the PFL-treated groups showed significant attenuations in all of the above parameters. Using lipopolysaccharide (LPS)-stimulated BV-2 cells, a murine microglial cell line, we measured PFL-mediated changes on the production of nitric oxide (NO), TNF-α, and IL-6, and the activities of their upstream MAP kinases (MAPKs)/NFκB/inducible NO synthase (iNOS). The LPS-induced upregulations of NO, TNF-α, and IL-6 production and MAPKs/NFκB/iNOS activities were globally and significantly reversed by 12-h pretreatment of PFL. This suggests that PFL can counteract VaD-associated structural and functional deterioration through the attenuation of neuroinflammation. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Graphical abstract

16 pages, 4635 KiB

Open AccessArticle

Low p-SYN1 (Ser-553) Expression Leads to Abnormal Neurotransmitter Release of GABA Induced by Up-Regulated Cdk5 after Microwave Exposure: Insights on Protection and Treatment of Microwave-Induced Cognitive Dysfunction

by Wei-Jia Zhi, Si-Mo Qiao, Yong Zou, Rui-Yun Peng, Hai-Tao Yan, Li-Zhen Ma, Ji Dong, Li Zhao, Bin-Wei Yao, Xue-Long Zhao, Xin-Xing Feng, Xiang-Jun Hu and Li-Feng Wang

Curr. Issues Mol. Biol. 2022, 44(1), 206-221; https://doi.org/10.3390/cimb44010015 - 31 Dec 2021

Cited by 2 | Viewed by 1918

Abstract

With the wide application of microwave technology, concerns about its health impact have arisen. The signal transmission mode of the central nervous system and neurons make it particularly sensitive to electromagnetic exposure. It has been reported that abnormal release of amino acid neurotransmitters [...] Read more.

With the wide application of microwave technology, concerns about its health impact have arisen. The signal transmission mode of the central nervous system and neurons make it particularly sensitive to electromagnetic exposure. It has been reported that abnormal release of amino acid neurotransmitters is mediated by alteration of p-SYN1 after microwave exposure, which results in cognitive dysfunction. As the phosphorylation of SYN1 is regulated by different kinases, in this study we explored the regulatory mechanisms of SYN1 fluctuations following microwave exposure and its subsequent effect on GABA release, aiming to provide clues on the mechanism of cognitive impairment caused by microwave exposure. In vivo studies with Timm and H&E staining were adopted and the results showed abnormality in synapse formation and neuronal structure, explaining the previously-described deficiency in cognitive ability caused by microwave exposure. The observed alterations in SYN1 level, combined with the results of earlier studies, indicate that SYN1 and its phosphorylation status (ser-553 and ser62/67) may play a role in the abnormal release of neurotransmitters. Thus, the role of Cdk5, the upstream kinase regulating the formation of p-SYN1 (ser-553), as well as that of MEK, the regulator of p-SYN1 (ser-62/67), were investigated both in vivo and in vitro. The results showed that Cdk5 was a negative regulator of p-SYN1 (ser-553) and that its up-regulation caused a decrease in GABA release by reducing p-SYN1 (ser-553). While further exploration still needed to elaborate the role of p-SYN1 (ser-62/67) for neurotransmitter release, MEK inhibition had was no impact on p-Erk or p-SYN1 (ser-62/67) after microwave exposure. In conclusion, the decrease of p-SYN1 (ser-553) may result in abnormalities in vesicular anchoring and GABA release, which is caused by increased Cdk5 regulated through Calpain-p25 pathway after 30 mW/cm² microwave exposure. This study provided a potential new strategy for the prevention and treatment of microwave-induced cognitive dysfunction. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

26 pages, 24815 KiB

Open AccessArticle

Biological Implications of a Stroke Therapy Based in Neuroglobin Hyaluronate Nanoparticles. Neuroprotective Role and Molecular Bases

by María Ángeles Peinado, David Ovelleiro, María Luisa del Moral, Raquel Hernández, Esther Martínez-Lara, Eva Siles, José Rafael Pedrajas, María Luisa García-Martín, Carlos Caro, Sebastián Peralta, María Encarnación Morales, María Adolfina Ruiz and Santos Blanco

Int. J. Mol. Sci. 2022, 23(1), 247; https://doi.org/10.3390/ijms23010247 - 27 Dec 2021

Cited by 4 | Viewed by 3691

Abstract

Exogenous neuroprotective protein neuroglobin (Ngb) cannot cross the blood–brain barrier. To overcome this difficulty, we synthesized hyaluronate nanoparticles (NPs), able to deliver Ngb into the brain in an animal model of stroke (MCAO). These NPs effectively reached neurons, and were microscopically identified after [...] Read more.

Exogenous neuroprotective protein neuroglobin (Ngb) cannot cross the blood–brain barrier. To overcome this difficulty, we synthesized hyaluronate nanoparticles (NPs), able to deliver Ngb into the brain in an animal model of stroke (MCAO). These NPs effectively reached neurons, and were microscopically identified after 24 h of reperfusion. Compared to MCAO non-treated animals, those treated with Ngb-NPs showed survival rates up to 50% higher, and better neurological scores. Tissue damage improved with the treatment, but no changes in the infarct volume or in the oxidative/nitrosative values were detected. A proteomics approach (p-value < 0.02; fold change = 0.05) in the infarcted areas showed a total of 219 proteins that significantly changed their expression after stroke and treatment with Ngb-NPs. Of special interest, are proteins such as FBXO7 and NTRK2, which were downexpressed in stroke, but overexpressed after treatment with Ngb-NPs; and ATX2L, which was overexpressed only under the effect of Ngb. Interestingly, the proteins affected by the treatment with Ngb were involved in mitochondrial function and cell death, endocytosis, protein metabolism, cytoskeletal remodeling, or synaptic function, and in regenerative processes, such as dendritogenesis, neuritogenesis, or sinaptogenesis. Consequently, our pharmaceutical preparation may open new therapeutic scopes for stroke and possibly for other neurodegenerative pathologies. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

15 pages, 1306 KiB

Open AccessBrief Report

High Caloric Diet Induces Memory Impairment and Disrupts Synaptic Plasticity in Aged Rats

by Sara L. Paulo, Catarina Miranda-Lourenço, Rita F. Belo, Rui S. Rodrigues, João Fonseca-Gomes, Sara R. Tanqueiro, Vera Geraldes, Isabel Rocha, Ana M. Sebastião, Sara Xapelli and Maria J. Diógenes

Curr. Issues Mol. Biol. 2021, 43(3), 2305-2319; https://doi.org/10.3390/cimb43030162 - 18 Dec 2021

Cited by 8 | Viewed by 2949

Abstract

The increasing consumption of sugar and fat seen over the last decades and the consequent overweight and obesity, were recently linked with a deleterious effect on cognition and synaptic function. A major question, which remains to be clarified, is whether obesity in the [...] Read more.

The increasing consumption of sugar and fat seen over the last decades and the consequent overweight and obesity, were recently linked with a deleterious effect on cognition and synaptic function. A major question, which remains to be clarified, is whether obesity in the elderly is an additional risk factor for cognitive impairment. We aimed at unravelling the impact of a chronic high caloric diet (HCD) on memory performance and synaptic plasticity in aged rats. Male rats were kept on an HCD or a standard diet (control) from 1 to 24 months of age. The results showed that under an HCD, aged rats were obese and displayed significant long-term recognition memory impairment when compared to age-matched controls. Ex vivo synaptic plasticity recorded from hippocampal slices from HCD-fed aged rats revealed a reduction in the magnitude of long-term potentiation, accompanied by a decrease in the levels of the brain-derived neurotrophic factor receptors TrkB full-length (TrkB-FL). No alterations in neurogenesis were observed, as quantified by the density of immature doublecortin-positive neurons in the hippocampal dentate gyrus. This study highlights that obesity induced by a chronic HCD exacerbates age-associated cognitive decline, likely due to impaired synaptic plasticity, which might be associated with deficits in TrkB-FL signaling. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

15 pages, 2490 KiB

Open AccessArticle

A Link between Mitochondrial Dysregulation and Idiopathic Autism Spectrum Disorder (ASD): Alterations in Mitochondrial Respiratory Capacity and Membrane Potential

by Hazirah Hassan, Fazaine Zakaria, Suzana Makpol and Norwahidah Abdul Karim

Curr. Issues Mol. Biol. 2021, 43(3), 2238-2252; https://doi.org/10.3390/cimb43030157 - 16 Dec 2021

Cited by 6 | Viewed by 2888

Abstract

Autism spectrum disorder (ASD) is a neurological disorder triggered by various factors through complex mechanisms. Research has been done to elucidate the potential etiologic mechanisms in ASD, but no single cause has been confirmed. The involvement of oxidative stress is correlated with ASD [...] Read more.

Autism spectrum disorder (ASD) is a neurological disorder triggered by various factors through complex mechanisms. Research has been done to elucidate the potential etiologic mechanisms in ASD, but no single cause has been confirmed. The involvement of oxidative stress is correlated with ASD and possibly affects mitochondrial function. This study aimed to elucidate the link between mitochondrial dysregulation and idiopathic ASD by focusing on mitochondrial respiratory capacity and membrane potential. Our findings showed that mitochondrial function in the energy metabolism pathway was significantly dysregulated in a lymphoblastoid cell line (LCL) derived from an autistic child (ALCL). Respiratory capacities of oxidative phosphorylation (OXPHOS), electron transfer of the Complex I and Complex II linked pathways, membrane potential, and Complex IV activity of the ALCL were analyzed and compared with control cell lines derived from a developmentally normal non-autistic sibling (NALCL). All experiments were performed using high-resolution respirometry. Respiratory capacities of OXPHOS, electron transfer of the Complex I- and Complex II-linked pathways, and Complex IV activity of the ALCL were significantly higher compared to healthy controls. Mitochondrial membrane potential was also significantly higher, measured in the Complex II-linked pathway during LEAK respiration and OXPHOS. These results indicate the abnormalities in mitochondrial respiratory control linking mitochondrial function with autism. Correlating mitochondrial dysfunction and autism is important for a better understanding of ASD pathogenesis in order to produce effective interventions. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

20 pages, 3912 KiB

Open AccessArticle

The Protective Mechanism of Deuterated Linoleic Acid Involves the Activation of the Ca²⁺ Signaling System of Astrocytes in Ischemia In Vitro

by Egor A. Turovsky, Elena G. Varlamova, Sergey V. Gudkov and Egor Y. Plotnikov

Int. J. Mol. Sci. 2021, 22(24), 13216; https://doi.org/10.3390/ijms222413216 - 08 Dec 2021

Cited by 14 | Viewed by 2439

Abstract

Ischemia-like (oxygen-glucose deprivation, OGD) conditions followed by reoxygenation (OGD/R) cause massive death of cerebral cortex cells in culture as a result of the induction of necrosis and apoptosis. Cell death occurs as a result of an OGD-induced increase in Ca²⁺ ions in [...] Read more.

Ischemia-like (oxygen-glucose deprivation, OGD) conditions followed by reoxygenation (OGD/R) cause massive death of cerebral cortex cells in culture as a result of the induction of necrosis and apoptosis. Cell death occurs as a result of an OGD-induced increase in Ca²⁺ ions in the cytosol of neurons and astrocytes, an increase in the expression of genes encoding proapoptotic and inflammatory genes with suppression of protective genes. The deuterated form of linoleic polyunsaturated fatty acid (D4-Lnn) completely inhibits necrosis and greatly reduces apoptotic cell death with an increase in the concentration of fatty acid in the medium. It was shown for the first time that D4-Lnn, through the activation of the phosphoinositide calcium system of astrocytes, causes their reactivation, which correlates with the general cytoprotective effect on the cortical neurons and astrocytes in vitro. The mechanism of the cytoprotective action of D4-Lnn involves the inhibition of the OGD-induced calcium ions, increase in the cytosolic and reactive oxygen species (ROS) overproduction, the enhancement of the expression of protective genes, and the suppression of damaging proteins. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

11 pages, 2194 KiB

Open AccessArticle

Farnesol Ameliorates Demyelinating Phenotype in a Cellular and Animal Model of Charcot-Marie-Tooth Disease Type 1A

by Na-Young Park, Geon Kwak, Hyun-Myung Doo, Hye-Jin Kim, So-Young Jang, Yun-Il Lee, Byung-Ok Choi and Young-Bin Hong

Curr. Issues Mol. Biol. 2021, 43(3), 2011-2021; https://doi.org/10.3390/cimb43030138 - 13 Nov 2021

Cited by 3 | Viewed by 3491

Abstract

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disease affecting the peripheral nervous system that is caused by either the demyelination of Schwann cells or degeneration of the peripheral axon. Currently, there are no treatment options to improve the degeneration of peripheral nerves in [...] Read more.

Charcot-Marie-Tooth disease (CMT) is a genetically heterogeneous disease affecting the peripheral nervous system that is caused by either the demyelination of Schwann cells or degeneration of the peripheral axon. Currently, there are no treatment options to improve the degeneration of peripheral nerves in CMT patients. In this research, we assessed the potency of farnesol for improving the demyelinating phenotype using an animal model of CMT type 1A. In vitro treatment with farnesol facilitated myelin gene expression and ameliorated the myelination defect caused by PMP22 overexpression, the major causative gene in CMT. In vivo administration of farnesol enhanced the peripheral neuropathic phenotype, as shown by rotarod performance in a mouse model of CMT1A. Electrophysiologically, farnesol-administered CMT1A mice exhibited increased motor nerve conduction velocity and compound muscle action potential compared with control mice. The number and diameter of myelinated axons were also increased by farnesol treatment. The expression level of myelin protein zero (MPZ) was increased, while that of the demyelination marker, neural cell adhesion molecule (NCAM), was reduced by farnesol administration. These data imply that farnesol is efficacious in ameliorating the demyelinating phenotype of CMT, and further elucidation of the underlying mechanisms of farnesol’s effect on myelination might provide a potent therapeutic strategy for the demyelinating type of CMT. Full article

(This article belongs to the Topic Neuroprotection by Drugs, Nutraceuticals and Physical Activity)

► Show Figures

Figure 1

Topic Menu

Topic Editors

Neuroprotection by Drugs, Nutraceuticals and Physical Activity

Topic Information

Keywords

Participating Journals

Published Papers (25 papers)

Further Information

Guidelines

MDPI Initiatives

Follow MDPI